Pre-surgical cryoablation in ≤ 2 cm ER + /HER2-tumors. Prognostic factors for the presence of residual invasive carcinoma.

BACKGROUND: Breast cancer remains the most commonly diagnosed cancer in women. Breast-conserving surgery (BCS) is the standard approach for small low-risk tumors. If the efficacy of cryoablation is demonstrated, it could provide a minimally invasive alternative to surgery. PURPOSE: To determine the success of ultrasound-guided cryoablation in achieving the absence of Residual Invasive Cancer (RIC) for patients with ER + /HER2- tumors ≤ 2cm and sonographically negative axillary nodes. MATERIALS AND METHODS: This prospective study was carried out from April 2021 to June 2023, and involved 60 preoperative cryoablation procedures on ultrasound-visible, node-negative (cN0) infiltrating ductal carcinomas (IDC). Standard diagnostic imaging included mammography and tomosynthesis, supplemented by ultrasound-guided biopsy. MRI was performed in patients with associated intraductal carcinoma (DCIS) and an invasive component on core needle biopsy (18 out of 22 cases). All tumors were tagged with ferromagnetic seeds. A triple-phase protocol (freezing-thawing-freezing) with Argon was used, with an average procedure duration of 40 min. A logistic regression model was applied to determine significant correlation between RIC and the study variables. RESULTS: Fifty-nine women (mean age 63 ± 8 years) with sixty low-risk unifocal IDC underwent cryoablation prior to surgery. Pathological examination of lumpectomy specimens post-cryoablation revealed RIC in only one of 38 patients with pure IDC and in 4 of 22 mixed IDC/DCIS cases. All treated tumors had clear surgical margins, with no significant procedural complications. CONCLUSIONS: Cryoablation was effective in eradicating 97% of pure infiltrating ER + /HER2-tumors ≤ 2cm, demonstrating its potential as a surgical alternative in selected patients.

Topical Meloxicam Hydroxypropyl Guar Hydrogels Based on Low-Substituted Hydroxypropyl Cellulose Solid Dispersions.

Meloxicam (MX) is a poorly water-soluble drug with severe gastrointestinal side effects. Topical hydrogel of hydroxypropyl guar (HPG) was formulated using a solid dispersion (SD) of MX with hydroxypropyl cellulose (LHPC) as an alternative to oral administration. The development of a solid dispersion with an adequate MX:LHPC ratio could increase the topical delivery of meloxicam. Solid dispersions showed high MX solubility values and were related to an increase in hydrophilicity. The drug/polymer and polymer/polymer interactions of solid dispersions within the HPG hydrogels were evaluated by SEM, DSC, FTIR, and viscosity studies. A porous structure was observed in the solid dispersion hydrogel MX:LHPC (1:2.5) and its higher viscosity was related to a high increase in hydrogen bonds among the -OH groups from LHPC and HPG with water molecules. In vitro drug release studies showed increases of 3.20 and 3.97-fold for hydrogels with MX:LHPC ratios of (1:1) and (1:2.5), respectively, at 2 h compared to hydrogel with pure MX. Finally, a fitting transition from zero to first-order model was observed for these hydrogels containing solid dispersions, while the n value of Korsmeyer-Peppas model indicated that release mechanism is governed by diffusion through an important relaxation of the polymer.

Tratamiento percutáneo del cáncer infiltrante de mama en estado clínico I/II mediante crioablación en pacientes sin indicación de cirugía axilar / Percutaneous cryoablation of clinical stage I/II breast cancer in patients without indication for axillary surgery

Objetivo: revisar la eficacia del tratamiento percutáneo del cáncer infiltrante de mama (CM) mediante crioablación guiada con ecografía en pacientes con estadio clínico I/II en las que se desestima la cirugía axilar. Métodos: se recogieron de nuestros archivos las pacientes con CM en estadio clínico I/II que fueron tratadas mediante crioablación guiada con ecografía en las que se desestimó la cirugía axilar. Se seleccionaron las pacientes que tuvieron un seguimiento mínimo de 12 meses. Las revisiones fueron ecográficas: la primera entre 1 y 2 meses (para valorar lesiones residuales por tratamiento incompleto) y posteriormente semestrales (para valorar las recidivas). Las lesiones residuales y las recidivas se confirmaron con BAG y en todos los casos se valoró el tratamiento con nueva crioablación (de rescate). Se analizó la eficacia del procedimiento en función del control local en la mama. Resultados: desde marzo de 2019 hasta septiembre de 2022 fueron tratadas mediante crioablación guiada con ecografía 84 pacientes con 92 CM en estadio clínico I/II en las que la cirugía axilar fue desestimada. Se estudiaron retrospectivamente las 43 pacientes (58-96 años, media 83, DE ±7,64) con 48 CM (entre 5 y 60 mm, media 17, DE ±13,75) que tuvieron un seguimiento mínimo de 12 meses (entre 12 y 40 meses, media 20). Hubo 2 pacientes con tratamiento incompleto en la primera ecografía y 5 pacientes recidivaron (entre 9 y 27 meses, media 17). Todas se trataron con crioablaciones de rescate. El control local a los 12 meses fue del 90,5% (probabilidad 0,905 error estándar 0,045) y en el 95% de las pacientes (41/43) se consiguió controlar localmente el CM. Fallecieron 6 pacientes, 3 por evolución del CM y 3 por otras causas. Todos los procedimientos fueron bien tolerados y no hubo complicaciones graves. (AU)

Objective: To review the efficacy of percutaneous treatment of infiltrating breast cancer (BC) by ultrasound-guided cryoablation in patients with clinical stage I/II without indication for axillary surgery Methods: Patients with clinical stage I/II BC who were treated by ultrasound-guided cryoablation in whom axillary surgery was ruled out were collected from our files. Patients who had a minimum follow-up of 12 months were selected. The ultrasound follow up were: the first between 1-2 months (to assess residual lesions due to incomplete treatment) and subsequently every six months (to assess recurrences). Residual lesions and recurrences were confirmed with CNB and in all cases treatment with new (salvage) cryoablation was considered. The efficacy of the procedure was assessed on local control in the breast. Results: Between March 2019 and September 2022, 84 patients with 92 BC in clinical stage I/II were treated with ultrasound-guided cryoablation without indication for axillary surgery. The inclusion criteria of the retrospective study were met by 43 patients (58-96 years, mean 83, SD ±7,64) with 48 BC (between 5-60mm, mean 17, SD ±13,75) who were reviewed during a mean period of 20 months (between 12-40 months). There were two patients with incomplete treatment at the first ultrasound and five patients relapsed (between 9-27 months, mean 17). All were treated with salvage cryoablation. Local control at 12 months was 90.5% (probability 0.905 standard error 0.045) and in 95% of patients (41/43) the BC was locally controlled. Six patients died, three due to progression of the BC and three due to other causes. All procedures were well tolerated and there were no serious complications. (AU)

Sentinel Node Biopsy in Patients With Breast Carcinoma Without Axillary Involvement at Diagnosis Receiving Primary Systemic Therapy.

BACKGROUND: Primary systemic therapy (PST) has acquired great importance in breast cancer (BC) in the last few years. In this scenario, even if it is accepted to perform SLNB before PST, most of the guidelines remark the advantages of this practice after it, such as avoiding another surgery to the patient, a rapid start of the treatment and no need of axillary dissection in cases of pathologic complete response (pCR). Nevertheless, the lack of knowledge of the initial axillary state and the need to practice axillary dissection with any axillary disease are claimed to be some other disadvantages. There are no randomized studies yet that can conclude the optimal timing of SLNB in PST, so for the moment we may settle for our common practice. PATIENTS AND METHODS: We studied all the cases attended in the Breast Unit that joined the inclusion criteria between 2011 and 2019 in our hospital and we compared the group with SLNB before PST with the group with SLNB after PST in terms of unnecessary axillary dissection and description features. RESULTS: We included 223 female patients diagnosed with BC and without clinical nor radiological axillary disease (cN0), who had received NAC and SLNB performed before or after it. We observed a higher proportion of high-grade histological tumors (G3), tumors with aggressive phenotypes (Basal like and Her 2 enriched), and younger women in the group of SLNB before NAC compared with the SLNB after NAC group (P < .01). Despite this, we did not find any difference in the number of positive SLNBs or in the number of ALND performed between the 2 groups. We found a higher proportion of ALND with all the lymph node (LN) negatives in the SLNB before NAC group. CONCLUSION: Taking into account that in the observation period we did not use ACOSOG Z0011 criteria with all the SLNBs, we figure out what would have been the real results nowadays following these criteria. In this scenario we conclude that patients with luminal phenotype seemed to benefit from practicing SLNB before NAC in terms of avoiding axillary dissections. We could not make any conclusion in the rest of the phenotypes. However, prospective studies are needed to confirm if this affirmation could be proved.

Multiparticulate Systems of Meloxicam for Colonic Administration in Cancer or Autoimmune Diseases.

The aim of this research is the development of new colonic release systems of meloxicam (MLX) a non-steroidal anti-inflammatory drug (NSAIDs) with pH and time-dependent vehicles for cancer or autoimmune diseases. The colon has a higher pH than the rest of the gastrointestinal tract (GIT) and this can be used as a modified release strategy. Eudragit® polymers are the most widely used synthetic products in the design of colonic release formulations because they might offer mucoadhesiveness and pH-dependent release. Colonic delivery systems produced with pH-dependent and permeable polymers (FS-30D) or with pH-independent and low permeability polymers (NM-30D), must dissolve at a pH range of 6.0-7.0 to delay the release of the drug and prevent degradation in the GIT, before reaching the colon. The conditions prepared to simulate a gastrointestinal transit showed the CNM multiparticulate system, composed of Eudragit® NM and cellulose, as the best release option for MLX with a more sustained release with respect to the other formulations. CNM formulation followed Higuchi and First-order release kinetics, thus MLX release was controlled by a combination of diffusion and polymers swelling/eroding processes.

One and Two-Step In Vitro-In Vivo Correlations Based on USP IV Dynamic Dissolution Applied to Four Sodium Montelukast Products.

Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to check its performance by establishing a level-A in vitro-in vivo correlation (IVIVC). During the development of a generic film-coated tablet formulation, two clinical trials were done with three different experimental formulations to achieve a similar formulation to the reference one. A dissolution test procedure with a flow-through cell (USP IV) was used to predict the in vivo absorption behavior. The method proposed is based on a flow rate of 5 mL/min and changes of pH mediums from 1.2 to 4.5 and then to 6.8 with standard pharmacopoeia buffers. In order to improve the dissolution of montelukast, sodium dodecyl sulfate was added to the 4.5 and 6.8 pH mediums. Dissolution profiles in from the new method were used to develop a level-A IVIVC. One-step level-A IVIVC was developed from dissolution profiles and fractions absorbed obtained by the Loo-Riegelman method. Time scaling with Levy's plot was necessary to achieve a linear IVIVC. One-step differential equation-based IVIVC was also developed with a time-scaling function. The developed method showed similar results to a previously proposed biopredictive method for montelukast, and the added value showed the ability to discriminate among different release rates in vitro, matching the in vivo clinical bioequivalence results.

Severe systemic delayed dermatitis in a patient with nickel-titanium sterilization microinserts perforating the uterus.

We report a case of severe systemic delayed dermatitis in a patient with nickel-titanium sterilization microinserts placement complicated by uterine perforation and polyethylene terephthalate (PET) exposure. We hypothesize that delayed dermatitis may be caused by the exposure of PET fibers in this patient with underlying autoimmune disorder. Further research on the use of PET and the potential of systemic dermatologic reactions when exposure occurs is needed, especially when considering the inclusion of PET in future implant device development.

Plasmocitoma mamario y cáncer de mama: a propósito de un caso / Breast Plasmacytoma and breast cancer: a case report

El plasmocitoma mamario es una neoplasia de células plasmáticas extremadamente infrecuente, con menos de cincuenta casos descritos en el último siglo. Por este motivo, apenas se dispone de datos acerca del abordaje, tratamiento y seguimiento más convenientes. Presentamos el caso de una paciente de 70 años que debutó con un plasmocitoma mamario y que un año después fue diagnosticada de un carcinoma mamario lobulillar ipsilateral. La asociación entre plasmocitoma y cáncer de mama no está descrita en la literatura, por lo que es muy complicado establecer un vínculo entre ambas entidades. Sin embargo, el abordaje terapéutico del plasmocitoma podría comprometer el tratamiento ulterior de un cáncer de mama, por lo que el tratamiento idóneo en estos casos sea probablemente la cirugía.

Breast plasmocytoma is an extremely rare plasma cell neoplasm, with less than 50 cases reported in the last century. This is the reason why we barely have data about optimal management, treatment and follow-up. We hereby report the case of a 70 year old woman diagnosed with breast plasmocytoma that developed lobular breast cancer a year later. The link between plasmocytoma and breast cancer has not been previously established. However, breast plasmocytoma treatment could compromise latter breast cancer approach, so probably the most suitable strategy in these cases should be breast surgery.Conclusions: There are clinical characteristics associated with complications in women with surgical management abortion in our center, such as admission diagnosis, unplanned pregnancy, previous abortion and type of evacuation. There are limitations regarding the quantity and quality of information, however, our results allow us to know the profile of patients treated for abortion in our center.

Empleo actual de la hormonoterapia neoadyuvante en cáncer de mama: resultados de una encuesta realizada en España / Current use of neoadjuvant endocrine treatment for breast cancer: results of a survey conducted in Spain

OBJETIVO: Establecer el estado actual del empleo de hormonoterapia en neoadyuvancia (HTNA) en las distintas unidades de patología mamaria del territorio nacional. MATERIAL Y MÉTODOS: Se confeccionó una encuesta electrónica de 14 preguntas que se envió a los socios de la Sociedad Española de Senología y Patología Mamaria (SESPM) así como a miembros de otros centros del ámbito público y privado. RESULTADOS: Se obtuvieron 79 respuestas. El 74,7% correspondían a centros del ámbito público. El 77,2% afirman emplear HTNA, si bien la mayoría (44,3%) solo en caso de mujeres ancianas pluripatológicas. El seguimiento de las pacientes corre a cargo del oncólogo médico en el 62,0% de los casos, siendo la exploración (64,7%), la resonancia (55,9%) y la ecografía los métodos más empleados en el seguimiento. El fármaco más utilizado es el letrozol (45,5%) y la duración habitual del tratamiento es de 3-6meses en casi de la mitad de los casos (43,0%). El 82,2% de los encuestados afirman realizar HTNA en caso de axila positiva, si bien casi la mitad (47,6%) la restringen al caso de mujer anciana con comorbilidad. La alternativa en caso de no respuesta es la cirugía en el 78,5% de los casos. El 72,2% de los encuestados creen que la posibilidad de realizar una plataforma genómica en la biopsia inicial les animaría a emplear más la HTNA. CONCLUSIONES: La HTNA es un método empleado por las unidades de mama de forma habitual, si bien su uso queda relegado por lo general a mujeres ancianas con comorbilidades

OBJECTIVES: To establish the current state of the use of neoadjuvant endocrine treatment (NET) for breast cancer in breast cancer units (BCU) in Spain. MATERIAL AND METHODS: A 14-question electronic survey was designed and sent on-line to members of the Spanish Society of Senology and Breast Disease (SESPM) as well as to other breast cancer units in public and private healthcare centres in Spain. RESULTS: A total of 79 surveys were completed. Nearly three quarters (74.7%) of respondents worked in public centres, and 77.2% used NET, although most (44.3%) only used it in elderly or frail women. Follow-up was carried out by a medical oncologist in 62.0% of the cases. The preferred follow-up methods were clinical examination (64.7%), MRI (55.9%) and ultrasound (48.5%). Letrozole was the chosen drug in 45.5%, and 43.0% maintained treatment for 3-6months. Most (82.2%) respondents used NET when there were axillary-positive nodes but, of these, 47.6% restricted it to frail elderly women. Surgery was the alternative treatment in 78.5% of non-responders. In all, 72.2% of the respondents believed that the possibility of performing a genomic profile in the core biopsy would increase the chances of NET use. CONCLUSIONS: NET is a frequently employed method in BCUs in Spain, although its use is usually relegated to elderly or frail women

Fibromatosis mamaria. Reporte de dos casos clínicos y revisión bibliogáfica / Mammary fibromatosis. Two case report and review of literatura

RESUMEN Introducción y objetivos: La fibromatosis produce tumores benignos pero localmente agresivos, que afectan a los tejidos blandos. A nivel mamario, representa tan sólo el 0.2% de las neoplasias de la mama. Nuestro objetivo con el presente artículo es profundizar en el conocimiento de la fibromatosis mamaria, a través del estudio de dos casos clínicos, mostrando sus características clínico-radiológicas e histológicas, e intentar establecer un protocolo de actuación adecuado. Métodos: Estudio retrospectivo de dos casos clínicos de fibromatosis mamaria diagnosticados en el Hospital Universitario La Paz entre los años 2018 y 2019. Resultados: Presentaremos dos pacientes con diagnóstico de fibromatosis mamaria, ambas debutaron con la autopalpación de un nódulo mamario. Al realizarles una ecografía, se visualizó un nódulo sólido, mal definido y axila ecográficamente negativa, que precisó de biopsia-aspiración con aguja gruesa. En los dos casos, se decidió resección quirúrgica de la lesión. Seguimiento mediante exploración mamaria y pruebas de imagen periódicas. Conclusiones: Aunque se trata de una entidad benigna, la fibromatosis mamaria puede simular un proceso maligno, tanto clínica como radiológicamente, por lo que precisa de un estudio histológico. A pesar de que la diseminación metastásica es muy poco frecuente, no se debe olvidar el carácter agresivo a nivel local de esta patología, y sus altas tasas de recurrencia. Como tratamiento, se debe realizar una resección quirúrgica, aunque recientemente se ha contemplado la opción de vigilancia estrecha sin tratamiento. No existe evidencia científica que justifique la utilización de otros tratamientos como la radioterapia o el tratamiento hormonal.

ABSTRACT Introduction and objectives: Fibromatosis produces benign but locally aggressive tumours that affect soft tissues. At breast level, it represents only 0.2% of breast neoplasms. Our goal with this article is to increase knowledge on breast fibromatosis, through the study of two clinical cases; explaining their clinical-radiologic and histological characteristics. Additionally, try to establish an adequate protocol, for the management of the disease and for its subsequent monitoring. Methods: A retrospective study about two clinical cases of breast fibromatosis diagnosed in La Paz Hospital between 2018-2019. Results: both patients presented with clinical manifestations, autopalpation of a breast nodule. A breast ultrasound was performed and a solid nodule was visualized, with poorly defined edges and ecographically negative armpit. A core needle biopsy was performed to confirm the histological diagnosis. In both clinical cases, the treatment was surgical resection of the lesion. Periodic revisions are being performed in order to exclude recurrence. Conclusions: Although it is a benign disease, breast fibromatosis can simulate a malignancy, both in a clinical and radiological way, so histological study is mandatory in order to achieve an accurate diagnosis. Even metastatic dissemination is extremely rare, the local aggressive nature and high rates of recurrence for fibromatosis makes surgical excision, with wide free margins, the most important tool in treatment, although the possibility of close surveillance without treatment is recently being contemplated. There is no scientific evidence to justify the use of other treatments such as radiotherapy or hormonal treatment.

Investigation on the Existence of Sex-By-Formulation Interaction in Bioequivalence Trials.

The US Food and Drug Administration recommends that if a drug product is intended for use in both sexes, similar proportions should be recruited for bioequivalence (BE) studies. In contrast, in Europe, subjects can belong to either sex. Literature suggesting the existence of sex-by-formulation interaction (S × F) is limited to few studies. To investigate if S × F is observed, this work includes 120 BE studies. Differences larger than 20% between the ratio test/reference of women and men or statistically significant S × F occurred in 25 of 120 studies (20.8%). The prevalence is higher in small studies (36.00% vs. 16.8%). Large differences between the ratios of the sex groups are the tails of the distribution. Two studies were repeated, and the differences between the ratios of the sex groups disappeared. The 90% confidence intervals of S × F did not confirm any relevant S × F. There is no evidence to require studies in both sex groups, combined or separately.

Sex-by-formulation interaction in bioequivalence trials with transdermal patches.

PURPOSE: The existence of a sex-by-formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males may not be representative of the results obtained in females and vice versa. The best evidence of the existence of a sex-by-formulation interaction has been obtained from a study conducted with transdermal patches. This observation might be caused by the different characteristics of the skin of males and females. The purpose of this work is to investigate the existence of a sex-by-formulation interaction in all bioequivalence studies of transdermal patches submitted to the Spanish Agency for Medicines between 2010 and 2016. METHODS: Only five different products (Buprenorphine-1, Fentantyl-1, Fentanyl-2, Rivastigmine-1 and Rivastigmine-2) that were submitted for registration included nine bioequivalence studies conducted in males and females. As single dose and multiple dose studies are required for registration of transdermal patches in the European Union, more than one study may be available to confirm the existence of a sex-by-formulation interaction. RESULTS: A sex-by-formulation interaction is suggested in six out of 27 datasets (22%), corresponding to two products, and it is statistically significant in three of them (11%). CONCLUSIONS: The sex-by-formulation interaction detected in some pharmacokinetic parameters of some studies is excluded when the study is repeated, which shows that these results are not reproducible. There is no evidence to require bioequivalence demonstration for transdermal patches in males and females separately.

Leiomioma vaginal con núcleos atípicos. Informe de un caso / Vaginal leiomyoma with bizarre nuclei. A case report

Resumen ANTECEDENTES: Los tumores vaginales benignos son excepcionales: papilomas, hemangiomas, pólipos y leiomiomas. Estos últimos son los más raros (4-5% de todas las neoplasias vaginales) pues solo se han reportado alrededor de 300 casos. CASO CLÍNICO: Paciente de 47 años, acudió a la consulta ginecológica con una tumoración vaginal de dos meses de evolución, sin manifestaciones clínicas adicionales. En la exploración física se observó una tumoración elástica, en la cara posterolateral derecha de la vagina. La ecografía transvaginal no mostró la alteración. Después del tratamiento expectante inicial, en la siguiente revisión se comprobó el rápido crecimiento de la lesión y la manifestación de los síntomas vaginales. Se decidió la extirpación quirúrgica de la lesión. El estudio anatomopatológico reportó un leiomioma vaginal, con células con núcleos atípicos. Durante el seguimiento la paciente permaneció asintomática, sin signos de recidiva local. CONCLUSIÓN: Si bien los leiomiomas son los tumores benignos más frecuentes en mujeres en edad reproductiva, su manifestación vaginal es excepcional. El diagnóstico definitivo se establece en el estudio anatomopatológico y el tratamiento de elección es la extirpación quirúrgica completa. Los tumores con elevada celularidad, alta concentración de células atípicas y actividad mitótica incrementada pueden tener un comportamiento benigno. Las recidivas también son excepcionales.

Abstract BACKGROUND: Benign vaginal tumors are a very rare entity which includes papillomas, hemangiomas, polyps and leiomyomas. Leiomyomas are especially infrequent, constituting only 4-5% of all vaginal tumors. In literature, about 300 cases have been reported. CLINICAL CASE: 47-year-old patient, who attended a gynecological consultation with a vaginal tumor of two months evolution, without additional clinical manifestations. Physical examination refers to an elastic tumor on the right posterolateral aspect of the vagina. The transvaginal ultrasound did not show the alteration. After the initial expected treatment, in the following review the rapid growth of the lesion was observed, in addition to the manifestation of vaginal symptoms. Surgical removal of the lesion will be applied. The anatomopathological study reported a vaginal leiomyoma, and cells with bizarre nuclei. During the follow-up, the asymptomatic patient was observed, without signs of local recurrence. CONCLUSION: Although leiomyomas represent the most frequent benign tumors in women of reproductive age, their vaginal manifestation is exceptional. The gold treatment is complete surgical extirpation and the definitive diagnosis is established by anatomopathological study. Tumors with high cellularity, high concentration of bizarre cells and increased mitotic activity appear to have a benign behavior. Although it is rare, there are cases of recurrence.

Evaluation of sex-by-formulation interaction in bioequivalence studies of efavirenz tablets.

AIMS: The existence of a sex-by-formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males would not be representative of the results that would have been obtained in females and vice versa. Recently, a sex-by-formulation interaction has been reported in a study for efavirenz tablets. The purpose of this paper is to investigate whether a sex-by-formulation interaction is actually observed in the bioequivalence studies conducted with efavirenz tablets. METHODS: The existence of sex-by-formulation interaction was investigated in the two studies conducted in our centre, where the same test and reference products were investigated in a pilot study with 12 subjects and a pivotal study with 36 subjects. RESULTS: In the pilot study, the point estimates for the test/reference ratio of geometrics means of Cmax in females and males were more than 20% different (95.42% vs.79.38%, i.e., 120.21%), but in a subsequent pivotal study the difference was less than 2% (111.14% vs. 109.98%, i.e., 101.66%). CONCLUSIONS: A sex-by-formulation interaction is suggested in the study with a small sample size, but it disappears when the study is repeated with a larger sample size. In conclusion, the analysis of subgroups should be conducted with caution when the size of the subgroups is not powered to show bioequivalence. There seems to be no reason to require bioequivalence studies for efavirenz in both sexes.

Early treatment of Class III malocclusion with facemask therapy.

The facemask is a widely used device in the treatment of Class III malocclusion and is intended to anteriorly displace the superior maxilla or stimulate its growth in that direction. The main goal of this study was to evaluate the effects of treatment using orthopedic maxillary expansion with facemask therapy in patients with Class III malocclusion. Sixty-four patients, with a mean age of 8.14 ± 1.18 years at the start of treatment and a mean age of 9.78 ± 1.19 years at the end, were treated using orthopedic maxillary expansion and associated facemask therapy. The patients were evaluated using lateral head teleradiography before and after treatment, and the differences were analyzed. In addition, binary logistic regression was used as a model for predicting successful treatment. When comparing the changes achieved by treatment, statistically significant favorable changes were found at the skeletal level. Furthermore, an improvement in the airways at all levels was detected. Orthopedic maxillary expansion associated with facemask therapy has proven effective in treating early skeletal Class III malocclusion.

Orbital and conjunctival metastasis from lobular breast carcinoma.

This article examines the clinical presentation of ocular metastasis from an infiltrating lobular breast carcinoma. We examined a conjunctival biopsy from a 69-year-old woman who developed unilateral conjunctival inflammation together with a neurotrophic corneal ulcer and proptosis. Infiltrating lobular breast carcinoma (ILBC) was diagnosed using routine histology and immunohistochemistry. She had a past history of a hormone receptor-positive infiltrating ILBC 11 years ago with cutaneous and diffuse osteoblastic metastases, and she was kept under treatment with lezotrol. Treatment was initiated with systemic corticosteroids but an annular conjunctival perilimbal infiltration was found to have spread, which did not respond either to local radiotherapy (total dose 60 Gy, 2 Gy per day). A new extensive corneal epithelial defect recurred, and because it had not responded to matrix therapy agent (RGTA, Cacicol®) eye drops, autologous serum eye drops and a therapeutic contact lens, a permanent total tarsorrhaphy was performed. Progression of the diffuse bone metastases was detected and the treatment with lezotrol was replaced by fulvestrant.Infiltrating lobular breast carcinoma is a rare cause of conjunctival metastasis. This aggressive malignancy did not respond to external beam radiotherapy.

Evaluación de la respuesta patológica a la quimioterapia neoadyuvante en mama y axila según los fenotipos moleculares del cáncer de mama / Evaluation of pathological response to neoadjuvant chemotherapy in the breast and axilla according to molecular phenotypes of breast cancer

Objetivo. Evaluar la respuesta patológica a la quimioterapia neoadyuvante tanto en la mama como en la axila según los fenotipos moleculares de cáncer de mama. Pacientes y método. Estudio retrospectivo entre enero de 2011 y diciembre de 2014 que incluye a las pacientes con cáncer de mama infiltrante intervenidas tras tratamiento con quimioterapia neoadyuvante. Hemos considerado 5 fenotipos moleculares según los criterios de St. Gallen 2013. La respuesta patológica en mama y en axila se ha evaluado según los criterios de Sataloff. Resultados. Se recogen los datos de un total de 181 pacientes tratadas con quimioterapia neoadyuvante, de las que a 96 se les realizó linfadenectomía axilar. El 34,3% tenían un fenotipo molecular Her-2, 28,7% basal, 25,4% luminal B y 11,6% luminal A. En los luminal A, el 28,5% han tenido una respuesta patológica completa en la mama frente al 21,4% en la axila; en los luminal B, 34,7 frente al 13,7%; en los luminal B Her-2, 65 frente a 41,1%; en los Her-2, 95,4 frente a 70,5%; en los basales, 59,6 frente a 36,8%. Globalmente, la respuesta patológica completa en la mama ha sido del 55,2% frente al 35,4% en axila. Conclusiones. Los fenotipos moleculares Her-2 y basal presentan mayores tasas de respuesta patológica completa tras quimioterapia neoadyuvante. No existe correlación entre la respuesta patológica observada en la mama y en la axila. La respuesta axilar es, en términos generales, menor que en la mama (AU)

Objective. To evaluate pathological response to neoadjuvant chemotherapy in the breast and axilla according to the different molecular phenotypes of breast cancer. Patients and method. A retrospective study was performed between January 2011 and December 2014, including those patients with infiltrating carcinoma who underwent surgery after neoadjuvant chemotherapy. Five molecular phenotypes were considered according to St. Gallen's 2013 criteria. Pathological axillary and breast response were evaluated following the Sataloff system. Results. We analysed data from 181 patients treated with neoadjuvant chemotherapy. Of these, an axillary lymphadenectomy was performed in 96 patients. In total, 34.3% of the patients belonged to the Her-2 group, 28.7% to the basal group, 25.4% to the luminal B group and 11.6% to the luminal A group. In luminal A tumours, pathological complete response was observed in the breast in 28.5% of the patients and in the axilla in 21.4%; in luminal B group, 34.7 versus 13.7%; in luminal B-Her-2, 65 versus 41.1%; in Her-2 positive tumours, pathological complete response was observed in the breast in 95.4% of the patients versus 70.5% in the axilla; in the basal group, pathological complete response was achieved in the breast in 59.6% versus only 36.8% in the axilla. Overall, pathological complete response was observed in the breast in 55.2% compared with 35.4% in the axilla. Conclusions. Her-2 and basal phenotypes of breast cancer show better rates of complete pathological complete response after neoadjuvant chemotherapy. No correlation was found between pathological response in the breast and the axilla. Axillary response was worse than that found in the breast (AU)

Agitation Rate and Time for Complete Dissolution in BCS Biowaivers Based on Investigation of a BCS Biowaiver for Dexketoprofen Tablets.

The objective of the present work is to investigate the validity of the existing requirements for BCS biowaivers of immediate release products containing a class I drug in relation to the agitation rate (50 or 75 rpm in the paddle apparatus) and the time limit for complete dissolution (30 min) in the current biowaivers in vitro dissolution tests. Further, the possibility of extensions will be examined since it has been proposed that the time limit for complete dissolution should be revised to 60 min, and also, if cone formation occurs with apparatus 2 at 50 rpm, then a higher agitation rate is acceptable to eliminate it. The development of four generic dexketoprofen immediate release tablets is described. Dexketoprofen is the eutomer of ketoprofen. According to the BCS, dexketoprofen is a class I drug. Three out of the four products failed to show bioequivalence for Cmax in the initial bioequivalence study conducted with the product despite similar but nonrapid dissolution profiles at 50 rpm in the paddle apparatus, or similar and very rapid dissolution profiles at 75 rpm. In conclusion, these data indicate that BCS biowaivers for class I drugs should be granted only when dissolution with the paddle apparatus is complete in 30 min at 50 rpm. The time limit for complete dissolution should not be extended to 60 min. Furthermore, the agitation rate should not be increased to 75 rpm, even in the case of a coning effect.

Bioequivalence between generic tacrolimus products marketed in Spain by adjusted indirect comparison.

PURPOSE: The objective of the study was to investigate the relative bioavailability between the generic tacrolimus products that are presently authorized in Spain by adjusted indirect comparison. This was based on demonstration of bioequivalence with the reference product (Prograf, Astellas Pharma), which makes these generic tacrolimus products prescribable, switchable and therapeutically equivalent to the reference product; yet, according to Spanish legislation, only prescribers can switch tacrolimus-containing products. METHODS: Data from independent bioequivalence studies that compare each generic product with the reference product were combined by adjusted indirect comparisons to investigate the relative bioavailability between generic drug products, since there is no direct bioequivalence study comparing generics to each other. RESULTS: Eight generic tacrolimus products in the form of capsules are presently authorized in Spain, but only five are marketed. These eight products represent only three different generic product developments. One product is authorized with four different names/companies, while another is authorized under three different names/companies. The adjusted indirect comparisons between generic products show bioequivalence within the conventional 80-125 % confidence interval acceptance criteria for area under the curve (AUC) and maximum concentration (Cmax). CONCLUSION: Not only are the generic products bioequivalent with the reference product, but also with each other.

Differences in lercanidipine systemic exposure when administered according to labelling: in fasting state and 15 minutes before food intake.

PURPOSE: The aim of this study was to compare the systemic exposure of lercanidipine (Zanidip) after oral administration in the fasted state and 15 min before food intake (meals) to investigate if the recommendations in the Summary of Product Characteristics (SPC) with respect to the intake of meals are adequate. METHODS: The results of three pilot bioequivalence studies performed to develop a lercanidipine generic product, where Zanidip was administered consistently as reference product in the fasted state or 15 min before a standard breakfast, were compared to estimate the drug­food interaction and the similarity of the methods of administration defined in the SPC. RESULTS: The ingestion of a standard (non-high-fat, non-high-calorie) meal 15 min after drug intake increased the area under the concentration­time curve (AUC(0-t)) of S-lercanidipine by 1.78-fold [90% confidence interval (CI) 1.48­2.15, P<0.0001] and the maximum concentration (Cmax) of Slercanidipine by 1.82-fold (90% CI 1.46­2.28, P<0.0001). These values are close to the twofold increase that has been described when Zanidip was taken immediately after a carbohydrate-rich meal. Higher levels would be expected with a high-fat, high-calorie meal. CONCLUSIONS: As intake with a carbohydrate-rich meal is not recommended in the SPC of Zanidip because a twofold difference was considered to be clinically relevant, the intake of lercanidipine only 15 min before food intake does not seem to be consistent with this recommendation. The Marketing Authorisation Holder should clarify the dosing instructions in relation to meals and identify a sufficient time-lapse to ensure an exposure similar to that obtained in phase III clinical efficacy studies.